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Transforming growth factor-beta initiates wound repair in rat liver through induction of the EIIIA-fibronectin splice isoform.

ABSTRACT: A prominent feature of the hepatic response to injury is production of a fetal isoform of fibronectin, a splice variant containing the EIIIA region, which appears very early after injury and derives from sinusoidal endothelial cells. Previous studies have shown that it is instrumental in initiating the cellular response to injury, specifically the conversion of resting stellate cells to myofibroblast-like cells. The present work describes the regulation of this change in fibronectin expression. Using sinusoidal endothelial cells from normal or injured liver in primary culture, we show that exogenous transforming growth factor beta (TGFbeta) stimulates [EIIIA]Fn expression. To assess the role of TGFbeta in vivo, we used a chimeric IgG containing the extracellular portion of the TGFbeta type II receptor as a competitive inhibitor of the cytokine. Administered to animals at the time of injury, the inhibitor reduced expression of [EIIIA]Fn mRNA by 50% as compared to controls (P < 0.01). There was a corresponding decrease in [EIIIA]Fn protein production as judged by immunohistochemistry. Cell fractionation experiments indicated that the changes observed in whole-liver extracts were localized to sinusoidal endothelial cells. We conclude that TGFbeta initiates wound repair in part by stimulating endothelial expression of [EIIIA]Fn. Results with the soluble inhibitor of the TGFbeta type II receptor suggest a novel strategy for modulating wound repair in vivo.

SUBMITTER: George J

PROVIDER: S-EPMC1868619 | biostudies-literature | 2000 Jan

REPOSITORIES: biostudies-literature

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Transforming growth factor-beta initiates wound repair in rat liver through induction of the EIIIA-fibronectin splice isoform.

George J J Wang S S SS Sevcsik A M AM Sanicola M M Cate R L RL Koteliansky V E VE Bissell D M DM

The American journal of pathology 20000101 1

A prominent feature of the hepatic response to injury is production of a fetal isoform of fibronectin, a splice variant containing the EIIIA region, which appears very early after injury and derives from sinusoidal endothelial cells. Previous studies have shown that it is instrumental in initiating the cellular response to injury, specifically the conversion of resting stellate cells to myofibroblast-like cells. The present work describes the regulation of this change in fibronectin expression. ...[more]

PMID: 10623659

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Project description:Transforming growth factor-?s (TGF-?s) regulate cellular proliferation, differentiation, and survival. TGF-?s bind to type I (TGF-?RI) and II receptors (TGF-?RII), which are transmembrane kinase receptors, and an accessory type III receptor (TGF-?RIII). TGF-? may utilize another type I receptor, activin-like kinase receptor (Alk1). TGF-? is neuroprotective in the middle cerebral artery occlusion (MCAO) model of stroke. Recently, we reported the expression pattern of TGF-?1-3 after MCAO. To establish how TGF-?s exert their actions following MCAO, the present study describes the induction of TGF-?RI, RII, RIII and Alk1 at 24 h, 72 h and 1 mo after transient 1 h MCAO as well as following 24 h permanent MCAO using in situ hybridization histochemistry. In intact brain, only TGF-?RI had significant expression: neurons in cortical layer IV contained TGF-?RI. At 24 h after the occlusion, no TGF-? receptors showed induction. At 72 h following MCAO, all four types of TGF-? receptors were induced in the infarct area, while TGF-?RI and RII also appeared in the penumbra. Most cells with elevated TGF-?RI mRNA levels were microglia. TGF-?RII co-localized with both microglial and endothelial markers while TGF-?RIII and Alk1 were present predominantly in endothels. All four TGF-? receptors were induced within the lesion 1 mo after the occlusion. In particular, TGF-?RIII was further induced as compared to 72 h after MCAO. At this time point, TGF-?RIII signal was predominantly not associated with blood vessels suggesting its microglial location. These data suggest that TGF-? receptors are induced after MCAO in a timely and spatially regulated fashion. TGF-? receptor expression is preceded by increased TGF-? expression. TGF-?RI and RII are likely to be co-expressed in microglial cells while Alk1, TGF-?RII, and RIII in endothels within the infarct where TGF-?1 may be their ligand. At later time points, TGF-?RIII may also appear in glial cells to potentially affect signal transduction via TGF-?RI and RII.

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Dataset Information

Transforming growth factor-beta initiates wound repair in rat liver through induction of the EIIIA-fibronectin splice isoform.

Publications

Transforming growth factor-beta initiates wound repair in rat liver through induction of the EIIIA-fibronectin splice isoform.

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